RT Journal Article
SR Electronic
T1 Evaluation of Muscarinic Agonist-Induced Analgesia in Muscarinic Acetylcholine Receptor Knockout Mice
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1084
OP 1093
DO 10.1124/mol.62.5.1084
VO 62
IS 5
A1 Alokesh Duttaroy
A1 Jesus Gomeza
A1 Jai-Wei Gan
A1 Nasir Siddiqui
A1 Anthony S. Basile
A1 W. Dean Harman
A1 Philip L. Smith
A1 Christian C. Felder
A1 Allan I. Levey
A1 Jürgen Wess
YR 2002
UL http://molpharm.aspetjournals.org/content/62/5/1084.abstract
AB Centrally active muscarinic agonists display pronounced analgesic effects. Identification of the specific muscarinic acetylcholine receptor (mAChR) subtype(s) mediating this activity is of considerable therapeutic interest. To examine the roles of the M2 and M4 receptor subtypes, the two Gi/Go-coupled mAChRs, in mediating agonist-dependent antinociception, we generated a mutant mouse line deficient in both M2 and M4 mAChRs [M2/M4 double-knockout (KO) mice]. In wild-type mice, systemic, intrathecal, or intracerebroventricular administration of centrally active muscarinic agonists resulted in robust analgesic effects, indicating that muscarinic analgesia can be mediated by both spinal and supraspinal mechanisms. Strikingly, muscarinic agonist-induced antinociception was totally abolished in M2/M4 double-KO mice, independent of the route of application. The nonselective muscarinic agonist oxotremorine showed reduced analgesic potency in M2 receptor single-KO mice, but retained full analgesic activity in M4 receptor single-KO mice. In contrast, two novel muscarinic agonists chemically derived from epibatidine, CMI-936 and CMI-1145, displayed reduced analgesic activity in both M2 and M4 receptor single-KO mice, independent of the route of application. Radioligand binding studies indicated that the two CMI compounds, in contrast to oxotremorine, showed >6-fold higher affinity for M4 than for M2 receptors, providing a molecular basis for the observed differences in agonist activity profiles. These data provide unambiguous evidence that muscarinic analgesia is exclusively mediated by a combination of M2 and M4 mAChRs at both spinal and supraspinal sites. These findings should be of considerable relevance for the development of receptor subtype-selective muscarinic agonists as novel analgesic drugs.